1. Field of the Invention
This invention generally relates to the field of main chain acid-degradable polymers for use in delivery of bioactive materials such as antigens, DNA and other therapeutics.
2. Description of the Related Art
Most materials for drug delivery systems are based on polyesters, which break down gradually for a slow consistent release of drug over time. However, it is important in many applications that the therapeutic be delivered and released quickly in the slightly acidic environment of endosomes or tumor tissue. Therefore several drug delivery systems have been designed to release their payload, small drugs or large biotherapeutics, upon a change in pH. Many different strategies have been employed such as attachment of the drug to a scaffold using a pH sensitive linkage, and encapsulation of the therapeutic in liposomes, micelles and particles that break apart or swell in an acidic environment leading to drug release.
Ideal drug delivery systems might have multiple functions, such as targeting the disease site and delivering the therapeutic to a specific site. Currently, there are several potential vehicles for drug delivery that are under investigation, each with their own set of advantages and disadvantages. Most materials for drug delivery systems are based on ester, amide or carbonate linkages, which break down gradually via base catalyzed hydrolysis for a slow consistent release of drug over time. However, there is a potential risk that extended clinical use of conjugates containing non or slow biodegradable polymer fragments can lead to long-term vacuolization. To date, none of the available materials combines all the desirable properties such as, low immunological response, low toxicity and complete biodegradability.
Furthermore, few examples of drug delivery systems are based on polymers that can degrade into small molecules triggered by a small change in pH. Such polymers include poly(acetals) (see Brocchini et al, U.S. Pat. No. 6,828,412), poly(ketals) (see Khaja et al., Biomacromolecules, ASAP Article 10.1021/bm061234z S1525-7797(06) 01234-7 and Murthy et al., Bioconjugate Chem., 14 (2), 412-419, 2003), and polyorthoesters (see Ng, S., Y.; Taylor, M., S.; Heller, J. Macromolecules 1997, 30, 770-772). It is therefore of interest to develop another class of polymers, which result in full main-chain degradation and that exhibit an even faster degradation and are simple to prepare.
Polycations are a leading class of nonviral gene-delivery vehicles because of their molecular diversity that can be modified to tune their physiochemical properties. Polycations can easily condense DNA through ionic interaction. It was also observed that cationic particles are internalized by cells more easily than neutral ones. One novel class of cationic polymers, which is used for gene delivery, is poly(amidoamines). Poly(amidoamines) possess many desirable properties, such as water solubility, biodegradability, and low cytotoxicity for the development of site-specific gene delivery. Their toxicity was found in number of tests to be constantly lower by two or three orders of magnitude than that of poly-L-lysine. Enhanced degradability of the poly(amidoamines) not only improves biocompatibility but may also help the release of genes from the polymeric scaffold.
Another potential application of these acid-degradable polymer backbones is protein vaccine delivery. The development of protein-based vaccines requires a drug delivery system that undergoes degradation in mildly acidic environment of, for example, tumor and lysosomes. Currently, most available polymers cannot fulfill this requirement because they are composed of linkages that degrade by base catalyzed hydrolysis. Therefore, development of acid degradable polymers, preferably degrading with the formation of nontoxic, readily cleavable or metabolizable products, is of great need. A particle system based on polyacrylamide polymer cross-linked with acid degradable cross linker, has previously been reported for the delivery of proteins. Acid degradable protein loaded polymer particles showed promising results for antigen-based vaccine.
Others have attempted and describe degradable polymers such as Brocchini et al. in U.S. Pat. No. 6,828,412, using high amounts of polyethylene glycol to increase solubility and result in large PEG chain degradation products.
However, one limitation with previous particle systems is the possible long lasting circulation of polyacrylamide after the delivery of protein. To overcome this problem, the present invention describes a completely degradable polymer system, based on polymers such as polyamidoamines, polyureas and polyurethanes.